CN103040747B - Sodium fusidate lipidosome injection - Google Patents
Sodium fusidate lipidosome injection Download PDFInfo
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- CN103040747B CN103040747B CN201210551292.9A CN201210551292A CN103040747B CN 103040747 B CN103040747 B CN 103040747B CN 201210551292 A CN201210551292 A CN 201210551292A CN 103040747 B CN103040747 B CN 103040747B
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Abstract
The invention discloses sodium fusidate lipidosome injection and a preparation method thereof. The lipidosome injection is prepared from sodium fusidate, soya bean lecithin, cholesteryl succinate, poloxamer188, povidone and mannitol. The lipidosome injection has the advantages of small particle size and even distribution of lipidosome, excellent stability of preparation, good encapsulation efficiency and lower leakage rate, reduces the impurities and the toxic and side effects, and improves the product quality and the curative effect.
Description
Technical field
The present invention relates to a kind of lipidosome injection and method for making thereof, be specifically related to a kind of sodium fusidate lipidosome injection and method for making thereof, belong to technical field of medicine.
Background technology
Sodium fusidate, its chemical name is: 16 α-acetoxy-3 β, 11 beta-dihydroxy-4 β, 8 β, nor--5 β of 14 α-trimethyl-18-, 10 α-gallbladder steroid-(17Z)-17 (20), 24-diene-21-acid sodium, molecular formula: C
31h
47naO
6, molecular weight: 538.70, its structural formula is as follows:
Fusidic acid is colourless acicular crystal, is dissolved in the organic solvents such as ethanol, acetone, chloroform and pyridine, water insoluble.Sodium fusidate is white crystalline powder, soluble in water, and intravenous injection good absorbing has extremely strong penetrance to tissue and body fluid.Sodium fusidate is that the protein synthesis by anti-bacteria produces bactericidal action, and a series of gram-positive bacteriums are had to powerful antibacterial action.Staphylococcus, comprises the bacterial strain to penicillin, methicillin and other antibiotics drug resistance, all extremely sensitive to this product.Between other antibacterials of sodium fusidate and clinical use without cross resistance, but it is unstable that it places in acid solution, in the sodium fusidafe as injection description of clinical use, point out, if glucose injection agent peracid, solution can be emulsus and when pH value is lower than 7.4 time, this product can precipitate.Wang Yaqun, HPLC method is measured the content of sodium fusidafe as injection, < < Chinese Medicine guide > >, 18 phases in 2008, the 55th page.
When medicine mixes with sodium fusidate or meets during clinical use, there will be muddiness or precipitation.Reason may be: 1) acid stronger medicine, as vitamin C, ligustrazine phosphate etc. can be because reducing the pH of solvent, fusidic acid is isolated from sodium fusidate middle reaches, form muddy or precipitation, therefore selective solvent should be noted, if pharmacopeia regulation glucose injection pH scope is that 3.5～6.5 sodium fusidate are probably separated out precipitation within the scope of this pH.2) may be combined into the double salt that dissolubility is less with fusidic acid, easily form muddy or precipitation.3) contain multivalent ion as Ca
2+and Mg
2+deng medicine and sodium fusidate compatibility, may, by fusidic acid chelating salify, change its solubility behavior and form muddiness or precipitation.Therefore sodium fusidate has alkalescence, sequestration properties, avoids clinically with faintly acid, polyvalent metal ion compound compatibility and uses.
The sodium fusidafe as injection preparation technology of domestic production is at present freeze-drying, in its preparation prescription, only there is principal agent sodium fusidate, every attached dedicated solvent of sodium fusidafe as injection preparation, its main component is sodium hydrogen phosphate, citric acid, to finding that the quality of this product is unstable in its follow-up of quality process, related substance change is larger, occurs that opalescence phenomenon, visible foreign matters in various degree increases, clinical patient is used and has unsafe factor after compatibility.
Patent CN101143133A discloses a kind of sodium fusidate freeze-dried powder preparation, and it comprises following component and content (weight portion): sodium fusidate 450-550, glycine 30-500, arginine 40-600.Above-mentioned lyophilized injectable powder also can further comprise excipient as at least one in lactose, mannitol, sorbitol.Consumption is 1～10% of described lyophilized injectable powder percentage by weight.
Patent CN1101264089A discloses a kind of Fusidate sodium composition and lyophilized formulations preparation method thereof, and in this Fusidate sodium composition, the weight ratio of sodium fusidate, excipient, stabilizing agent/PH regulator is 25-100:2-100:1-50.Wherein excipient is preferably glucose and/or mannitol, and stabilizing agent/PH regulator is preferably a kind of or its mixture in arginine, disodiumedetate and calcio-disodium edetate.
Although the disclosed preparation prescription of above two patents is through meticulous screening, it there is no in fact difference, just the buffer salt in the appended dedicated solvent of former preparation has been added in preparation, has added again a large amount of stabilizing agents; Although preparation has facilitated clinical use, stability has also obtained some raisings, but related substance still increases obviously, while not solving medicine stability and clinical use there is not the problem of stimulation, pain in venipuncture place at all yet, therefore, this area is starved of makes product stability and the better preparation of clinical compatibility compliance by sodium fusidate, thoroughly to solve its stability problem, and improves bioavailability.
In pharmaceutical carrier induction system, the research of the submicrons such as microemulsion, microsphere, nanoparticle, liposome, pharmacosomes has become very active field in novel pharmaceutical formulation research.Drug encapsulation can be changed in these submicrons to medicine distribution in vivo, increase medicine in the abundance of target organ, thereby improve curative effect, alleviate toxic and side effects.
In targeting drug delivery system, the research of liposome is comparatively extensive, and liposome has good targeting and biocompatibility in vivo.As a kind of new medicinal preparation, Liposomal formulation has the following advantages: (1) has slow releasing function: active component slowly discharges, and delays renal excretion and metabolism, thereby extends action time, improves mass effect; (2) increase the dissolubility of medicine, improve the quality of the pharmaceutical preparations; (3) there is targeting: the contained medicine of liposome maintains high concentration in liver, spleen reticuloendothelial system internal organs part, thereby plays the effect of medicine organ targeting; (4) there is the protective effect to active pharmaceutical ingredient; (5) reduced drug toxicity.
Summary of the invention
The stability of liposome is to limit for a long time the major issue of liposome extensive use, liposome ubiquity is easily assembled, is merged, cause entrapped drug to leak, therefore in industrial preparation, meet the real non-easy thing of medicinal liposome of stability requirement, the technical staff that pharmaceutical field has a universal experience knows clearly and faces all difficulties preparing aspect medicinal liposome, all these existing absolutely not theories can be expected solution need to overcome many difficult problems.Therefore need to find by every means the liposome prescription of optimization, to obtain the liposome of excellent in stability, to meet the demand of the current sodium fusidate lipidosome injection for sodium fusidate lipidosome injection especially excellent in stability.
The inventor is surprised to find that through large quantity research, by selecting sodium fusidate, cholesterol succinate, soybean lecithin, PLURONICS F87, mannitol and the polyvidone of specified weight proportioning, can form the sodium fusidate lipidosome injection of excellent quality, thereby complete the present invention.
Lipidosome injection of the present invention has reduced toxic and side effects, has improved formulation products quality, has good preparation stability, and after long term storage, liposome keeps good envelop rate equally.
The sodium fusidate lipidosome injection making by the inventive method, improved the dissolubility of sodium fusidate, improved the quality of formulation products, delayed the release of sodium fusidate, increased the retention time of medicine in body circulation, the bioavailability that has improved medicine, has reduced toxic and side effects, and curative effect obviously improves; And preparation method is simple, be suitable for industrialized great production.
In order to form colory sodium fusidate lipidosome injection, thereby importantly find, can good compatible with sodium fusidate it well be sealed and non-leakage filmogen, and find the excipient composition that can make liposome form stable injectable agent.
To achieve these goals, large quantity research and realization that the inventor carries out, find the sodium fusidate of specified weight proportioning, soybean lecithin, cholesterol succinate, PLURONICS F87, polyvidone and mannitol can be made excellent sodium fusidate lipidosome injection, wherein, envelop rate as the sodium fusidate of active constituents of medicine is high, liposome particle diameter is little and be evenly distributed, compare with fusidic acid sodium injection of the prior art, the retention time significant prolongation of the active constituents of medicine of preparation of the present invention in body circulation, the biocompatibility of medicine is high, bioavailability obviously improves, curative effect obviously improves.
Especially, as one aspect of the present invention, the inventor surprisingly finds, in the water of sodium fusidate, adds polyvidone, is particularly conducive to the dispersion of sodium fusidate and improves sealing of medicine, thereby excellent sodium fusidate lipidosome injection is provided.
The invention provides a kind of sodium fusidate lipidosome injection, it is made by the medicine and the excipient composition that comprise following weight proportion:
Condition is: the weight ratio between cholesterol succinate and soybean lecithin is 1:5-1:3, preferably 1:4.
Preferably, sodium fusidate lipidosome injection of the present invention is made by medicine and the excipient composition of following weight proportion:
Condition is: the weight ratio between cholesterol succinate and soybean lecithin is 1:5-1:3, preferably 1:4; And the weight ratio between polyvidone and soybean lecithin is 1:6-1:4.
As the phospholipid that is used to form liposome, generally can use natural phospholipid and synthetic phospholipid, comprise soy phosphatidylserine, Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, PI, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, PHOSPHATIDYL ETHANOLAMINE, soybean phospholipid acyl inositol, cholesterol, DOPC, DSPC, dipalmitoyl phosphatidyl choline, DMPC, DLPC, DOPG, DSPG, DPPG, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, PE, PEG-DSPE 2000, two soft ester acyl gallbladder phospholipid-Macrogol 2000s, HSPC-Macrogol 2000, DOPC-Macrogol 2000 etc.Inventor prepares in the test of liposome at the membrane material of the above-mentioned phospholipid of application and phospholipid and cholesterol combination, find that the liposome obtaining is like this under 40 ℃ of high temperature, relative humidity 75% ± 5% accelerated test, the stability of liposome and envelop rate are not good, therefore apply conventional phospholipid and or the liposome material of cholesterol cannot obtain meeting the object of the invention fusidic acid sodium lipidosome.
In the present invention, feature for sodium fusidate, the inventor finds to only have the combination of soybean lecithin and cholesterol succinate to be particularly suitable for the membrane material as sodium fusidate by research, can optimum solve the problems such as the stability of sodium fusidate liposome and envelop rate, obtained beyond thought preparation effect, thereby colory liposome is provided.
Soybean lecithin is as a kind of natural phospholipid, and its content is high, easily obtains, cheap, is easy to form stable liposome membrane.When using other phospholipid and cholesterol succinate combination, be difficult to form colory fusidic acid sodium lipidosome, the character such as the envelop rate of sodium fusidate, stability and percolation ratio are poor.
In sodium fusidate lipidosome injection of the present invention, for the sodium fusidate of 1 weight portion, the consumption of soybean lecithin is 10-18 weight portion.If the consumption of soybean lecithin, lower than 10 weight portions, cannot form stable liposome; Otherwise, if the consumption of the consumption of soybean lecithin higher than 20 weight portions, the envelop rate as the sodium fusidate of active constituents of medicine declines, the quality of injection and curative effect reduce.
In sodium fusidate lipidosome injection of the present invention, cholesterol succinate and PLURONICS F87 are used in particular for regulating the membrane stability of liposome, and can change the drug release behavior of sodium fusidate, be conducive to obtain the effect liposome of suitable release, for example once-a-day administration, and improve the bioavailability of sour sodium westernly.
Cholesterol succinate (cholesterol hemisuccinate, CHS) be the succinum ester derivant of cholesterol, have another name called Cholesteryl hemisuccinate, cholesterol hemisuccinate, cholesterol succinate, except bear electric charge, also has good liposome membrane Stabilization.The succinic acid derivative of this cholesterol, biodegradable in body, there is not security risks, can safety as elecrtonegativity materials'use.Cholesterol succinate is a kind of amphiphilic, combines with soybean lecithin, stops it to be condensed into crystal structure.Cholesterol succinate mixes soybean lecithin bilayer, is similar to " buffer agent " and equally plays the effect that regulates membrane structure " mobility ".When lower than phase transition temperature, cholesterol succinate can make film reduce ordered arrangement, increases mobility; When higher than phase transition temperature, cholesterol succinate can increase the ordered arrangement of film, thereby reduces the mobility of film.Cholesterol succinate can make liposome bi-layer membrane solidify, thereby reduces the generation of free radical, reduces oxidation level, and liposome stability is significantly strengthened.
The inventor finds through research, when cholesterol succinate and soybean lecithin weight ratio are 1:5-1:3, can form stable fusidic acid sodium lipidosome.When cholesterol succinate and soybean lecithin weight ratio are during higher than 1:3, sodium fusidate liposome membrane mobility is too high, and the sodium fusidate being wrapped in liposome is easy to discharge; When cholesterol succinate and soybean lecithin weight ratio are during lower than 1:5, membrane stability reduces, and sodium fusidate is easy to seepage.In addition, research finds, when cholesterol succinate and soybean lecithin weight ratio are 1:5-1:3, formed liposome toxicity is minimum.
In sodium fusidate lipidosome injection of the present invention, with PLURONICS F87, further improve the character of liposome membrane.PLURONICS F87 is a kind of non-ionic surface active agent, when for soybean lecithin duplicature, can improve the chemical energy between this duplicature, thereby improve the chemical stability of liposome in waterborne liquid, and then the stability of raising sodium fusidate lipidosome injection, and be conducive to sodium fusidate release.
In sodium fusidate lipidosome injection of the present invention, for the sodium fusidate of 1 weight portion, the consumption of PLURONICS F87 is 1-4 weight portion.If the consumption of PLURONICS F87 is lower than 1 weight portion, because its consumption is too low, cause the stability improvement of sodium fusidate lipidosome injection inadequate, otherwise, if the consumption of PLURONICS F87 is higher than 4 weight portions, too high for its consumption and cause liposome membrane to be easy to reveal.
Polyvidone, as dispersant, is particularly conducive to the dispersion of sodium fusidate in aqueous solution, is very beneficial for the stable of sodium fusidate and seals, thereby excellent sodium fusidate lipidosome injection can be provided.Experiment confirms, because can making water viscosity, the existence of polyvidone increases, being encapsulated in the middle moisture film of liposome makes water soluble drug have higher envelop rate, and can make medicine stable in storage, sodium fusidate of the present invention is dispersed in polyvidone, and be encapsulated in together in liposome, therefore from not the character containing the fusidic acid sodium lipidosome of polyvidone is completely different, and polyvidone has also delayed the release of sodium fusidate.
In sodium fusidate lipidosome injection of the present invention, for the sodium fusidate of 1 weight portion, the consumption of polyvidone is 1-6 part, preferably 2-4 part, if consumption is too low to be caused the envelop rate of sodium fusidate not highly, if consumption is too high, cause sodium fusidate to discharge slow.
In sodium fusidate lipidosome injection of the present invention, mannitol is as excipient, and form and stability that it can effectively protect liposome particles further improve the stability of lipidosome injection.
The stability of liposome and bioavailability have close corresponding relation.Stability is higher, and bioavailability is higher.Therefore, the stability of sodium fusidate lipidosome injection of the present invention is high, is to cause one of factor that drug bioavailability is high.
Research shows, when using the sodium fusidate, soybean lecithin, cholesterol succinate, polyvidone, mannitol of above-mentioned specified quantitative and PLURONICS F87, can obtain colory fusidic acid sodium lipidosome, its envelop rate and stability are all very high, toxicity is low, and bioavailability is high.
Sodium fusidate lipidosome injection of the present invention, its injection specification is the sodium fusidate containing 0.125g, 0.25g and 0.5g.
The present invention also provides a kind of preparation method of sodium fusidate lipidosome injection, specifically comprises and is prepared as follows step:
(1) sodium fusidate is dissolved in phosphate buffered solution, adds polyvidone, water stirs to obtain;
(2) soybean lecithin, cholesterol succinate and PLURONICS F87 are dissolved in organic solvent, stir and make its dissolving; Above-mentioned solution is placed in to eggplant-shape bottle, and organic solvent is removed in 45 ℃ of water-bath decompressions, on bottle wall, forms uniformly transparent film;
(3) under nitrogen protection, to the water that adds step 1 in bottle; Stir, make immobilized artificial membrane eluting fully swelling hydration, then at 300bar, to 600bar, do gradient homogenizing 4～6 times, 0.22 μ m filtering with microporous membrane, makes fusidic acid sodium lipidosome;
(4) under nitrogen protection, the fusidic acid sodium lipidosome that step (3) is made, regulates pH value to 5.0～6.0 by pH adjusting agent, 60 ℃ of water-baths 10～15 minutes, then cools the temperature to 20～30 ℃ and add mannitol under constantly stirring; Through 0.22 μ m filtering with microporous membrane, subpackage, directly lyophilization, obtains fusidic acid sodium injection lyophilized injectable powder.
Preparation method described above, wherein said phosphate buffered solution is that to be selected from pH be 7.0～9.8 phosphate buffered solution, is preferably pH and is 7.8 phosphate buffered solution.
Preparation method described above, wherein the organic solvent described in step (2) is selected from one or more in ethanol, chloroform, dichloromethane, methanol, n-butyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, the tert-butyl alcohol, normal hexane, the tert-butyl alcohol that preferred volume ratio is 3:1 and the mixed organic solvents of isopropyl alcohol.
Preparation method described above, wherein pH adjusting agent described in step (3) is a kind of in hydrochloric acid, carbonic acid, acetic acid, phosphoric acid and sulphuric acid, is preferably hydrochloric acid.
Preferably, the present invention also provides a kind of preparation method of sodium fusidate lipidosome injection, specifically comprises and is prepared as follows step:
(1) sodium fusidate is dissolved in to pH and, in 7.8 phosphate buffered solution, adds polyvidone, water stirs to obtain;
(2) soybean lecithin, cholesterol succinate and PLURONICS F87 being dissolved in to volume ratio is in the tert-butyl alcohol of 3:1 and the mixed organic solvents of isopropyl alcohol, stirs and makes its dissolving; Above-mentioned solution is placed in to eggplant-shape bottle, and organic solvent is removed in 45 ℃ of water-bath decompressions, on bottle wall, forms uniformly transparent film;
(3) under nitrogen protection, to the water that adds step 1 in bottle; Stir, make immobilized artificial membrane eluting fully swelling hydration, then at 300bar, to 600bar, do gradient homogenizing 4～6 times, 0.22 μ m filtering with microporous membrane, makes fusidic acid sodium lipidosome;
(4) under nitrogen protection, the fusidic acid sodium lipidosome that step (3) is made, regulates pH value to 5.0～6.0 by pH adjusting agent, 60 ℃ of water-baths 10～15 minutes, then cools the temperature to 20～30 ℃ and add mannitol under constantly stirring; Through 0.22 μ m filtering with microporous membrane, subpackage ,-50～-60 ℃ of pre-freezes 2～4 hours, then freezing 6～8 hours at-40 ℃～-50 ℃, through 12～24 hours, sublime up into 20 ℃～25 ℃ again, finally at 30 ℃～35 ℃, be dried 6～12 hours, obtain fusidic acid sodium injection lyophilized injectable powder.
One of challenge of preparing liposome is the high vesicle of envelop rate that how to make liposome membrane form well-balanced, suitable big or small appropriate configuration material, and the liposome that these materials form does not spill.The inventor, by selecting suitable material composition, adopting suitable preparation technology, has obtained colory sodium fusidate lipidosome injection, and liposome particle diameter is little, and particle size distribution is even, and envelop rate is high, and stability is high.
Research finds, the size of liposome is affect that liposome distributes in vivo and the principal element of the time of staying, and the particle diameter of liposome is less, and the interior time of staying of body is longer.The sodium fusidate liposome particles of preparing by the inventive method is little, and particle size distribution is even, and bioavailability is high.
Accompanying drawing explanation
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
Fig. 1 is the blood drug level-time graph of sodium fusidate lipidosome injection.From top to bottom, be respectively embodiment 1, embodiment 2, embodiment 3, comparative example 2, comparative example 3, comparative example 1 and commercially available prod in average blood drug level-time graph of 0.5h, 1h, 1.5h, 2h, 3h, 6h, 8h, 12h and 24h.
Wherein:
The specific embodiment
Further illustrate by the following examples the present invention, but should not be construed as limitation of the present invention.
the preparation of embodiment 1 sodium fusidate lipidosome injection
Prescription: (100 bottles)
Preparation process:
(1) 12.5g sodium fusidate is dissolved in the phosphate buffered solution that the pH of 5000ml is 7.8, adds 50g polyvidone, water stirs to obtain;
(2) 200g soybean lecithin, 50g cholesterol succinate and 25g PLURONICS F87 being dissolved in to 500ml volume ratio is in the tert-butyl alcohol of 3:1 and the mixed organic solvents of isopropyl alcohol, stirs and makes its dissolving; Above-mentioned solution is placed in to eggplant-shape bottle, and organic solvent is removed in 45 ℃ of water-bath decompressions, on bottle wall, forms uniformly transparent film;
(3) under nitrogen protection, to the water that adds step 1 in bottle; Stir, make immobilized artificial membrane eluting fully swelling hydration, then at 300bar, to 600bar, do gradient homogenizing 5 times, 0.22 μ m filtering with microporous membrane, makes fusidic acid sodium lipidosome;
(4) under nitrogen protection, the fusidic acid sodium lipidosome that step (3) is made, regulates pH value to 5.5 by pH adjusting agent, 60 ℃ of water-baths 13 minutes, then cools the temperature to 25 ℃ and add mannitol under constantly stirring; Through 0.22 μ m filtering with microporous membrane, 100 bottles of subpackages ,-56 ℃ of pre-freezes 3 hours, then-45 ℃ freezing 7 hours, then sublimed up into 23 ℃ through 18 hours, finally 32 ℃ dry 9 hours, obtain fusidic acid sodium injection lyophilized injectable powder.
the preparation of embodiment 2 sodium fusidate lipidosome injections
Prescription: (100 bottles)
Preparation process:
(1) 25g sodium fusidate is dissolved in the phosphate buffered solution that the pH of 5000ml is 7.8, adds 75g polyvidone, water stirs to obtain;
(2) 350g soybean lecithin, 87.5g cholesterol succinate and 50g PLURONICS F87 being dissolved in to 800ml volume ratio is in the tert-butyl alcohol of 3:1 and the mixed organic solvents of isopropyl alcohol, stirs and makes its dissolving; Above-mentioned solution is placed in to eggplant-shape bottle, and organic solvent is removed in 45 ℃ of water-bath decompressions, on bottle wall, forms uniformly transparent film;
(3) under nitrogen protection, to the water that adds step 1 in bottle; Stir, make immobilized artificial membrane eluting fully swelling hydration, then at 300bar, to 600bar, do gradient homogenizing 4 times, 0.22 μ m filtering with microporous membrane, makes fusidic acid sodium lipidosome;
(4) under nitrogen protection, the fusidic acid sodium lipidosome that step (3) is made, regulates pH value to 5.0 by pH adjusting agent, 60 ℃ of water-baths 10 minutes, then cools the temperature to 20 ℃ and add mannitol under constantly stirring; Through 0.22 μ m filtering with microporous membrane, 100 bottles of subpackages ,-50 ℃ of pre-freezes 2～4 hours, then-40 ℃ freezing 6～8 hours, then sublimed up into 20 ℃ through 12 hours, finally 30 ℃ dry 6 hours, obtain fusidic acid sodium injection.
the preparation of embodiment 3 sodium fusidate lipidosome injections
Prescription: (100 bottles)
Preparation process:
(1) 50g sodium fusidate is dissolved in to 10000mlpH and, in 7.8 phosphate buffered solution, adds 100g polyvidone, water stirs to obtain;
(2) 600g soybean lecithin, 150g cholesterol succinate and 100g PLURONICS F87 being dissolved in to 1200ml volume ratio is in the tert-butyl alcohol of 3:1 and the mixed organic solvents of isopropyl alcohol, stirs and makes its dissolving; Above-mentioned solution is placed in to eggplant-shape bottle, and organic solvent is removed in 45 ℃ of water-bath decompressions, on bottle wall, forms uniformly transparent film;
(3) under nitrogen protection, to the water that adds step 1 in bottle; Stir, make immobilized artificial membrane eluting fully swelling hydration, then at 300bar, to 600bar, do gradient homogenizing 6 times, 0.22 μ m filtering with microporous membrane, makes fusidic acid sodium lipidosome;
(4) under nitrogen protection, the fusidic acid sodium lipidosome that step (3) is made, regulates pH value to 6.0 by pH adjusting agent, 60 ℃ of water-baths 10～15 minutes, then cools the temperature to 30 ℃ and add mannitol under constantly stirring; Through 0.22 μ m filtering with microporous membrane, 100 bottles of subpackages ,-60 ℃ of pre-freezes 4 hours, then-50 ℃ freezing 8 hours, then sublimed up into 25 ℃ through 24 hours, finally 35 ℃ dry 12 hours, obtain fusidic acid sodium injection.
the preparation of comparative example 1-3 sodium fusidate lipidosome injection
Comparative example 1-3 adopts respectively and production technology identical in embodiment 1-3, and the composition in comparative example 1-3 is as shown in Table 1 below made respectively to sodium fusidate lipidosome injection:
Composition used in table 1 comparative example 1-3
| Composition | Comparative example 1 | Comparative example 2 | Comparative example 3 |
| Sodium fusidate | 12.5g | 25g | 50g |
| Ovum Gallus domesticus Flavus lecithin | 200g | / | / |
| Soybean lecithin | / | 350g | 600g |
| Cholesterol | / | 87.5g | / |
| Cholesterol succinate | 50g | / | 150g |
| Polyvidone | / | 20g | / |
| Gelatin | / | / | 100g |
| PLURONICS F87 | 25g | 50g | / |
| Poloxamer188 | / | / | 100g |
| Mannitol | / | 87.5g | 150g |
| Trehalose | 50g | / | / |
Wherein, "/" represents not use.
the mensuration of test example 1 liposome particle diameter
Under room temperature condition, get the sodium fusidate lipidosome injection in embodiment 1-3 and comparative example 1-3, be placed in the sample cell of Submicron Particle Sizer Model 370 particle diameter detectors, measure particle size distribution and mean diameter; With projection electron microscope, observe particle shape.The results are shown in following table 2.
Table 2 liposome particle diameter testing result
| Numbering | Mean diameter | Outward appearance |
| Embodiment 1 | 124.3nm | Spherical, evenly |
| Comparative example 1 | 167.5nm | Inhomogeneous, mixed and disorderly |
| Embodiment 2 | 132.6nm | Spherical, evenly |
| Comparative example 2 | 146.1nm | Inhomogeneous, mixed and disorderly |
| Embodiment 3 | 127.9nm | Spherical, evenly |
| Comparative example 3 | 152.6nm | Inhomogeneous, spherical |
As known from Table 2, the liposome particle diameter that embodiment 1-3 makes is even, aobvious spherical, big or small homogeneous; The liposome particle diameter that comparative example 1-3 makes is inhomogeneous, and shape is indefinite, not of uniform size.
Particularly, when adopting same production technology, comparative example's 1 use Ovum Gallus domesticus Flavus lecithin replaces the soybean lecithin of embodiment 1, replaces mannitol, and do not use polyvidone with trehalose; Comparative example's 2 use cholesterol replace the cholesterol succinate of embodiment 2, and the consumption of polyvidone is 0.8 part of lower deal outside the scope of the invention; Comparative example's 3 use gelatin replace the polyvidone of embodiment 3, with poloxamer188, replace PLURONICS F87; In embodiment 1-3, particle appearance and the particle size distribution thereof of gained fusidic acid sodium lipidosome are even, are obviously better than the mixed and disorderly fusidic acid sodium lipidosome of gained in comparative example 1-3.When the composition beyond using the present invention's composition used is described, or when composition consumption is outside the composition amount ranges of the present invention's restriction, the outward appearance of gained fusidic acid sodium lipidosome is inferior to the present invention, and particle size range is very large, and impact discharges the uniformity.
the mensuration of test example 2 envelop rates
Rotating speed high speed centrifugation by the sodium fusidate lipidosome injection of preparing in embodiment 1-3 and comparative example 1-3 with 5000r/min, centrifugal 20 minutes, gets supernatant, with methanol-water, dissolve, HPLC method is surveyed fusidic acid sodium content, and computational envelope rate, the results are shown in following table 3.
Table 3 entrapment efficiency determination result
The envelop rate of the Liposomal formulation that as shown in Table 3, prepared by embodiment 1-3 is significantly higher than the envelop rate of the Liposomal formulation of comparative example 1-3.When the composition beyond using the present invention's composition used is described, or when composition consumption is outside the composition amount ranges of the present invention's restriction, the liposome encapsulation of gained liposome is lower than the present invention.Particularly, not using, comparative example's 1 envelop rate of polyvidone is minimum, and comparative example 3 gelatin used is also conducive to improve envelop rate, but effect is not so good as polyvidone, and the polyvidone envelop rate of comparative example's 2 lower deals does not reach optimal value yet.
test example 3 study on the stability
Sample prepared by embodiment of the present invention 1-3 and listing fusidic acid sodium injection (lot number: 20110210, Mt. Tiantai, Chengdu pharmaceutical Co. Ltd, production address: lower 6 months of the condition that No. 88, Tian Xing main road, Qionglai City) is placed in respectively 40 ℃ of high temperature, relative humidity 75%, carry out accelerated test investigation, experimental result is shown in following table 4.
Table 4 accelerated test result
As shown in Table 4, while accelerating June, listing formulation content reduces, and related substance raises; And sample property of the present invention, content and related substance variation are all not obvious, related substance (impurity) also, lower than the disclosed data of CN101143133A table 2-8, illustrates that product stability of the present invention is good.
Particularly, comparative example 1-3 is also better than the preparation that goes on the market, wherein stability aspect comparative example 2 is the poorest in comparative example 1-3, may be that comparative example's 2 use cholesterol replace the cholesterol succinate of embodiment 2 to cause showing not due to bear electricity, it is stability influence aspect soybean lecithin+cholesterol succinate, also be better than soybean lecithin+cholesterol, comparative example 3 is not so good as embodiment 3 and with poloxamer188, replaces the reason of PLURONICS F87, embodiment 1-3 is significantly better than comparative example 1-3, when the composition beyond using the present invention's composition used is described, or in the time of outside the composition amount ranges that composition consumption limits in the present invention, the content of gained fusidic acid sodium lipidosome reduces, related substance raises, embodiment 1-3 stability height is the result of membrane material comprehensive function, also relevant to surfactant.
test example 4 percolation ratio tests
Get sample prepared by test example 1-3 and comparative example 1-3, at ambient temperature, respectively at 0 day, 30 days, 60 days, 90 days and 180 days, make regular check on, measure envelop rate, with the dose comparison of sealing for 0 day, calculate percolation ratio, the results are shown in following table 5.
Table 5 percolation ratio result of the test
As shown in Table 5, during long term storage, the sodium fusidate lipidosome injection percolation ratio of preparing in embodiment of the present invention 1-3 changes little, and the injection percolation ratio of preparing in comparative example 1-3 increases gradually, liposome seepage is serious, and sodium fusidate lipidosome injection prepared by this explanation the present invention has higher stability.Comparative example 1-3 also shows that in percolation ratio comparative example 2 is the poorest in comparative example 1-3, may be that comparative example's 2 use cholesterol replace the cholesterol succinate of embodiment 2 to cause showing not due to bear electricity.Embodiment 1-3 percolation ratio is low is the result of membrane material comprehensive function, also relevant to surfactant.
the mensuration of test example 5 blood drug level
56 rats are divided into 7 groups at random, every group of injection of preparing in drug administration by injection embodiment 1-3 and comparative example 1-3 respectively, and commercially available (lot number: 20110210, Mt. Tiantai, Chengdu pharmaceutical Co. Ltd, production address: No. 88, Tian Xing main road, Qionglai City), specification is 0.125g fusidic acid sodium injection.After administration, respectively at 0.5h, 1h, 1.5h, 2h, 3h, 6h, 8h, 12h and 24h, take a blood sample, blood sample after treatment, is measured blood drug level with HPLC-MS method.Sodium fusidate lipidosome injection and the blood drug level of commercially available fusidic acid sodium injection and the relation curve of time in the sodium fusidate lipidosome injection of preparing in drafting embodiment 1-3, comparative example 1-3, prepared, be shown in accompanying drawing 1.
From top to bottom, be respectively embodiment 1, embodiment 2, embodiment 3, comparative example 2, comparative example 3, comparative example 1 and commercially available prod, as shown in Figure 1, compare with commercially available sodium fusidate lipidosome injection with the sodium fusidate lipidosome injection of preparing in comparative example 1-3, the sodium fusidate lipidosome injection of preparing in embodiment of the present invention 1-3 has the following advantages: release rate is in vivo slow, in body circulation, distribution time extends, and has reached slow release effect, and bioavailability has improved.
The result of comparative example 1-3 in experimental example 1-5 confirmed that from different aspect the lipidosome injection of preparing embodiment of the present invention 1-3 has excellent galenic pharmacy feature, obtained collaborative windfall effect, solved galenic pharmacy technical problem, confirmed that component of the present invention has produced synergism each other.
industrial applicibility
From the result of above-described embodiment and experimental example, fusidic acid sodium lipidosome of the present invention has good outward appearance, and granule is little, and particle diameter is even, envelop rate is high, and stability is high, and percolation ratio is low, the time of staying is in vivo long, and bioavailability is high, has good industrial application value.
Below through the specific embodiment and the embodiment the present invention is had been described in detail; but should understand; these explanations do not form any restriction to scope of the present invention; in the case of without departing from the spirit and scope of protection of the present invention; can carry out multiple modification, improvement and replacement to technical solutions and their implementation methods of the present invention, because these all fall within the scope of protection of the present invention.
Each list of references of mentioning in the application or quoting, which is hereby incorporated by reference.
Claims (4)
1. a sodium fusidate lipidosome injection, its medicine by following weight proportion and excipient composition are made:
It is characterized in that the weight ratio between described polyvidone and soybean lecithin is 1:6-1:4, and the weight ratio between cholesterol succinate and soybean lecithin is 1:4.
2. sodium fusidate lipidosome injection according to claim 1, its injection specification is 0.125g, 0.25g and 0.5g.
3. a method of preparing sodium fusidate lipidosome injection described in claim 1, is characterized in that comprising the steps:
(1) sodium fusidate is dissolved in phosphate buffered solution, adds polyvidone, water stirs to obtain; Wherein said phosphate buffered solution is that pH is 7.8 phosphate buffered solution;
(2) soybean lecithin, cholesterol succinate and PLURONICS F87 are dissolved in organic solvent, stir and make its dissolving; Above-mentioned solution is placed in to eggplant-shape bottle, and organic solvent is removed in 45 ℃ of water-bath decompressions, on bottle wall, forms uniformly transparent film; Wherein said organic solvent is that volume ratio is the tert-butyl alcohol of 3:1 and the mixed organic solvents of isopropyl alcohol;
(3) under nitrogen protection, to the water that adds step 1 in bottle; Stir, make immobilized artificial membrane eluting fully swelling hydration, then at 300bar, to 600bar, do gradient homogenizing 4～6 times, 0.22 μ m filtering with microporous membrane, makes fusidic acid sodium lipidosome;
(4) under nitrogen protection, the fusidic acid sodium lipidosome that step (3) is made, regulates pH value to 5.0～6.0 by pH adjusting agent, 60 ℃ of water-baths 10～15 minutes, then cools the temperature to 20～30 ℃ and add mannitol under constantly stirring; Through 0.22 μ m filtering with microporous membrane, subpackage, directly lyophilization, obtains fusidic acid sodium injection lyophilized injectable powder.
4. method according to claim 3, the process that it is characterized in that the lyophilizing described in step (4) was :-50～-60 ℃ of pre-freezes 2～4 hours, then freezing 6～8 hours at-40 ℃～-50 ℃, through 12～24 hours, sublime up into 20 ℃～25 ℃ again, finally at 30 ℃～35 ℃, be dried 6～12 hours.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1816560A (en) * | 2003-07-16 | 2006-08-09 | 利奥制药有限公司 | Novel fusidic acid derivatives |
| CN102319215A (en) * | 2011-09-14 | 2012-01-18 | 海南灵康制药有限公司 | Vecuronium bromide liposome injection |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1816560A (en) * | 2003-07-16 | 2006-08-09 | 利奥制药有限公司 | Novel fusidic acid derivatives |
| CN102319215A (en) * | 2011-09-14 | 2012-01-18 | 海南灵康制药有限公司 | Vecuronium bromide liposome injection |
Non-Patent Citations (2)
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| 丁武孝等.琥珀酸胆固醇酯作为脂质体膜稳定剂的研究及其在制备柴胡皂苷-D脂质体中的应用.《药学学报》.2005,第40卷(第7期),第623-627页. |
| 琥珀酸胆固醇酯作为脂质体膜稳定剂的研究及其在制备柴胡皂苷-D脂质体中的应用;丁武孝等;《药学学报》;20051231;第40卷(第7期);第623-627页 * |
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